Transdermally deliverable opioid prodrugs, abuse-resistant compositions and methods of using opioid prodrugs

Abstract

Described herein are opioid prodrugs, methods of making opioid prodrugs, formulations comprising opioid prodrugs, and methods of using opioid prodrugs. One embodiment described herein relates to the transdermal administration of a buprenorphine prodrug in an abuse-resistant formulation for treating and preventing diseases and/or disorders.

1. A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of oxygenated alkyl carbonate, and oxygenated ester, wherein the oxygenated ester does not terminate in an —OH group. 
     
     
       2. The compound of  claim 1  wherein the oxygenated alkyl carbonate is a hydroxylated alkyl carbonate. 
     
     
       3. The compound of  claim 1  wherein the oxygenated alkyl carbonate is an oxa-carbonate. 
     
     
       4. The compound of  claim 3  wherein the oxa-carbonate is a pegylated carbonate. 
     
     
       5. The compound of  claim 1  wherein the oxygenated ester is an oxa-ester. 
     
     
       6. The compound of  claim 5  wherein the oxa-ester is pegylated ester. 
     
     
       7. A compound of  claim 1  having an in vitro transdermal flux enhancement of greater than one relative to buprenorphine. 
     
     
       8. A compound of  claim 1  having an in vitro transdermal flux (nmol/cm 2 /hr) greater than buprenorphine. 
     
     
       9. A compound of  claim 1  having a twenty-four hour cumulative amount (nmol) of in vitro transdermal permeation greater than buprenorphine. 
     
     
       10. A pharmaceutical composition comprising:
 (a) a buprenorphine prodrug selected from the group consisting of a compound having the formula: 
 
       
         
           
           
               
               
           
         
         
           wherein R 1  is selected from the group consisting of oxygenated alkyl carbonate, and oxygenated ester, wherein the oxygenated ester does not terminate in an —OH group; and 
         
         (b) a pharmaceutical excipient. 
       
     
     
       11. The pharmaceutical composition of  claim 10  further comprising a second compound selected from the group consisting of: naltrexone and prodrugs of naltrexone. 
     
     
       12. The pharmaceutical composition of  claim 10  further comprising a second compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of: H; —COC(CH 3 ) 3 ; —COCH(CH 3 ) 2 ; —COCH 2 CH(CH 3 ) 2 ; —COCH(CH 2 CH 3 ) 2 ; —CON(CH 2 CH 3 ) 2 ; —CON(CH(CH 3 ) 2 ) 2 ; —COOCH(CH 3 ) 2 ; 
       
       
         
           
           
               
               
           
         
       
       and —CO(CH 2 ) 2 OCH 3 . 
     
     
       13. The pharmaceutical composition of  claim 10  further comprising a second compound selected from the group consisting of: 3-O-pivalyl naltrexone; 3-O-isovaleryl naltrexone; 3-O-(2′-ethylbutyryl) naltrexone; 3-O-isobutyryl naltrexone; 3-O-isopropyloxycarbonyl naltrexone; 3-O-tertiarybutyloxycarbonyl naltrexone; N,N-dimethyl-3-O-carbamate naltrexone; N,N-diethyl-3-O-carbamate naltrexone; and N,N-diisopropyl-3-O-carbamate naltrexone. 
     
     
       14. A method of treating a medical condition in a mammal selected from the group consisting of: opioid dependence, alcohol dependence and pain comprising the step of transdermally administering to the mammal a buprenorphine prodrug from the group consisting of:
 a compound having the formula: 
 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from the group consisting of oxygenated alkyl carbonate, and oxygenated ester, wherein the oxygenated ester does not terminate in an —OH group. 
       
     
     
       15. The method of  claim 14  further comprising the step of transdermally administering to the mammal a second compound having the formula: 
       
         
           
           
               
               
           
         
         wherein R 3  is selected from the group consisting of: H; —COC(CH 3 ) 3 ; —COCH(CH 3 ) 2 ; —COCH 2 CH(CH 3 ) 2 ; —COCH(CH 2 CH 3 ) 2 ; —CON(CH 2 CH 3 ) 2 ; —CON(CH(CH 3 ) 2 ) 2 ; —COOCH(CH 3 ) 2 ; 
       
       
         
           
           
               
               
           
         
       
       and —CO(CH 2 ) 2 OCH 3 . 
     
     
       16. The method of  claim 14  further comprising the step of transdermally administering a second compound to the mammal selected from the group consisting of: naltrexone; 3-O-pivalyl naltrexone; 3-O-isovaleryl naltrexone; 3-O-(2′-ethylbutyryl) naltrexone; 3-O-isobutyryl naltrexone; 3-O-isopropyloxycarbonyl naltrexone; 3-O-tertiarybutyloxycarbonyl naltrexone; N,N-dimethyl-3-O-carbamate naltrexone; N,N-diethyl-3-O-carbamate naltrexone; and N,N-diisopropyl-3-O-carbamate naltrexone. 
     
     
       17. A method of transdermally administering a buprenorphine prodrug to a mammal comprising the steps of:
 (a) obtaining a pharmaceutical composition comprising:
 (i) a compound having the formula: 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein R 1  is selected from the group consisting of oxygenated alkyl carbonate, and oxygenated ester, wherein the oxygenated ester does not terminate in an —OH group; and 
           
           (ii) a pharmaceutically acceptable excipient; and 
         
         (b) contacting the pharmaceutical composition with the skin of the mammal. 
       
     
     
       18. A method for transdermally delivering a buprenorphine prodrug to a mammal comprising the steps of:
 (a) obtaining a pharmaceutical composition comprising:
 (i) a compound having the formula: 
 
 
       
         
           
           
               
               
           
         
         
           
             wherein R 1  is selected from the group consisting of oxygenated alkyl carbonate, and oxygenated ester, wherein the oxygenated ester does not terminate in an —OH group; and 
           
           (ii) a naltrexone prodrug having the formula: 
         
       
       
         
           
           
               
               
           
         
         
           
             wherein R 3  is selected from the group consisting of: H; —COC(CH 3 ) 3 ; —COCH(CH 3 ) 2 ; —COCH 2 CH(CH 3 ) 2 ; —COCH(CH 2 CH 3 ) 2 ; —CON(CH 2 CH 3 ) 2 ; —CON(CH(CH 3 ) 2 ) 2 ; —COOCH(CH 3 ) 2 ; 
           
         
       
       
         
           
           
               
               
           
         
         
           
              and —CO(CH 2 ) 2 OCH 3 ; and 
           
         
         (b) contacting the pharmaceutical composition with the skin of the mammal.